WO2002000681A1 - Steroïdes 20-fluoro-17(20)-vinyliques convenant comme inhibiteurs ce la c17-20-lyase et de la 5-alpha reductase - Google Patents

Steroïdes 20-fluoro-17(20)-vinyliques convenant comme inhibiteurs ce la c17-20-lyase et de la 5-alpha reductase Download PDF

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WO2002000681A1
WO2002000681A1 PCT/US2001/019889 US0119889W WO0200681A1 WO 2002000681 A1 WO2002000681 A1 WO 2002000681A1 US 0119889 W US0119889 W US 0119889W WO 0200681 A1 WO0200681 A1 WO 0200681A1
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bond
hydroxy
methyl
fluoro
alkyl
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Norton P. Peet
Philip M. Weintraub
Joseph P. Burkhart
Cynthia A. Gates
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Aventis Pharma SA
Aventis Pharmaceuticals Inc
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Aventis Pharma SA
Aventis Pharmaceuticals Inc
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Priority to EP01946642A priority Critical patent/EP1409512A1/fr
Priority to AU2001268661A priority patent/AU2001268661A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J13/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having a carbon-to-carbon double bond from or to position 17
    • C07J13/007—Normal steroids containing carbon, hydrogen, halogen or oxygen having a carbon-to-carbon double bond from or to position 17 with double bond in position 17 (20)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/28—Antiandrogens

Definitions

  • the present invention relates to 20-fluoropregna-5,17(20)-diene-3/3,21-diol, 20-fluoro-pregna-5, 17(20)- dien-3 ⁇ -ol and related compounds, to processes for their preparation, and to compositions incorporating these compounds as well as the use of these compounds in the treatment of conditions which would be affected by inhibition of Ci7 ; 20 lyase and/or 5 ⁇ -reductase, including androgen and estrogen mediated or dependent disorders, such as, for example benign prostatic hyperplasia; dihydrotestosterone-mediated disorders such as, for example, acne; estrogen dependent breast cancer and androgen mediated prostatic cancer.
  • the present invention provides a novel series of compounds which also disable the operation of Ci ⁇ -hydroxylase; thus, disorders that are characterized by an oversynthesis of cortisol can also be treated by the compounds of the invention. For example, hypokalemia, metabolic alkalosis, polydipsia, polyurea, Cushing's syndrome and hypertensive conditions.
  • the enzyme steroid C 1 20 lyase cleaves the 17-20 carbon-carbon bond in steroids having a two carbon side chain at the 17 ⁇ -carbon position to form important precursor molecules for the formation of testosterone, 5 -dihydrotestosterone and the estrogens, principally estrone and estradiol.
  • Compounds which inhibit this enzyme would thus serve to inhibit the formation of the indicated precursors and thereby be useful in the treatment of various androgenic as well as estrogenic disorders.
  • a treatment incorporating such enzymatic inhibitors is not limited to the origin of the precursor molecule, such as various organ ablation techniques which are currently known. For example, while orchiectomy will effectively reduce gonadal androgen, it will have not have significant effect upon adrenal androgen production.
  • Prostatic cancer or neoplastic tissue disorders which originate in the parenchymal epithelium of the prostate, is one of the most common malignancies among men, and exhibits one of the highest cancer-specific deaths of all malignant carcinomas. It is known that patients with metastatic prostate cancer respond positively to hormonal therapy. It is reported by Cookson and Sarosdy that androgen ablation has had a positive, beneficial response for as high as 60% to 80% of all patients tested. [Cookson, CS. and Sarosdy, M.F., South Med. J. 1994, 87, 1-6].
  • C ⁇ 7) 20 lyase inhibitors would be useful in the treatment of hormonal dependent prostatic carcinoma, prostatic hyperplasia, virilism, congenital adrenal hyperplasia due to 21 -hydroxylase deficiency, hirsutism, hormonal dependent breast cancer, polycystic ovarian syndrome correlated with elevated
  • C 17,20 lyase activity as well as other neoplastic tissue disorders such as endometrial, hepatocellular and adrenal carcinomas.
  • the enzyme steroid 5 ⁇ -reductase present in mammalian tissues including skin, male genitalia and the prostate, catalyzes the conversion of testosterone (17 ⁇ -hydroxyandrost-4-en-3-one) into dihydrotestosterone or DHT (17 ⁇ -hydroxy-5 ⁇ -androstan-3-one), which is also known as stanolone.
  • DHT is a more potent androgen than testosterone, and acts as an end-organ effector in certain tissues, particularly in mediating growth. DHT formation can occur in certain tissues themselves by the action of 5 ⁇ -reductase.
  • the conversion of testosterone to DHT itself can be associated with various androgenic disorders, especially when DHT levels build up to excessive amounts.
  • DHT DHT-associated disease 2019
  • acne vulgaris high levels of DHT in the skin has been associated in the pathogenesis of acne, including acne vulgaris.
  • androgen mediated or androgen dependent disorders such as acne, benign prostatic hyperplasia and prostatic cancer, including hormonal dependent carcinoma, the inhibition of DHT would be highly desirable.
  • the enzyme C ⁇ hydroxylase catalyzes the C ⁇ 7 hydroxylation of steroid substrates during the biosynthesis of cortisol.
  • C 1 ; 20 lyase and Cj 7 hydroxylase are the same active site of the same enzyme, the inhibition of one usually results in the inhibition of the other.
  • Cortisol excess results in a syndrome characterized by hypokalemia, metabolic alkalosis, polydipsia, polyuria, Cushing's syndrome and hypertensive conditions. Inhibition of cortisol synthesis via Cj 7 hydroxylase would, therefore, have a beneficial therapeutic effect for the treatment of these disorders or conditions.
  • the present invention is directed to a group of compounds, and to their pharmaceutically acceptable salts, of the formula:
  • Rl is H or C ⁇ _4 alkyl
  • R2 is H or C i-4 alkyl
  • R3 is H, chloro, nirro, amino or C ⁇ -4 alkyl
  • R4 is H or C i-4 alkyl
  • R5 is H or C i-4 alkyl
  • R6 is H or methyl
  • R7 is H or methyl
  • R8 is H or methyl
  • R9 is H or methyl; or R 8 and R 9 taken together is oxo;
  • R 10 is H or methyl
  • R n is H
  • R 12 is hydroxy; or R n and R 12 taken together is oxo; X is H, hydroxy or methoxy; with the proviso that when: a) R u is H and R 12 is hydroxy, bond C ⁇ 5 is a single bond, bond C 5,6 is a double bond and bond C ⁇ 5> ⁇ 6 is optionally a single bond or a double bond , and b) R u and R 12 taken together is oxo, bond C ⁇ 5 is a double bond, bond C 5j6 is a single bond, and bond C ⁇ 5) i6 is a single bond.
  • Another embodiement of the invention provides use of the compounds of the invention as inhibitors of Ci 7 , 2 o lyase and 5 ⁇ -reductase for the treatment of androgen or estrogen mediated or dependent disorders such as breast cancer, polycystic ovarian syndrome, prostatic hyperplasia, prostatic cancer, virilism, hirsutism, and acne.
  • the invention provides use of the compounds of the invention for the treatment of Cushing's syndrome.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier.
  • the compounds of the invention may be administered in combination with other effective treatments for enhanced therapeutic effect.
  • other effective treatments for enhanced therapeutic effect including prostatic cancer, flutamide, a known androgen receptor antagonist, may be used in combination with compounds of the invention.
  • a preferred embodiement of the invention are compounds wherein R 1 , R 2 , R 3 , R 4 , R 5 , R ⁇ , R 7 , R 8 , R 9 , R u and X are hydrogen, R 10 is methyl, R 12 is hydroxy, bond C 4j5 and bond C 15 ⁇ l6 are each a single bond and bond C 5]6 is a double bond.
  • a most preferred embodiement of the invention are compounds wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R n are hydrogen, R 10 is methyl, X and R 12 are each hydroxy, bond C ⁇ s and bond C 15 6 are each a single bond and bond Cs ⁇ is a double bond.
  • C1.4 alkyl means any straight or branched chain alkyl radical of one to four carbon atoms, for example, methyl, ethyl, n-propyl, z ' -propyl, «-butyl, s-butyl, or f-butyl.
  • ⁇ — is defined as a bond above the plane of the steroid (the ⁇ -face).
  • v ⁇ " is defined as a cis or trans bond (or mixture of the two) whose stereochemistry is not defined. is defined as an optional double bond.
  • pharmaceutically acceptable salt is intended to apply to any salt, whether previously known or future discovered, that is used by one skilled in the art that is a non-toxic organic or inorganic addition salt which is suitable for use as a pharmaceutical.
  • Illustrative bases which form suitable salts include alkali metal or alkaline-earth metal hydroxides such as sodium, potassium, calcium or magnesium hydroxides; ammonia and aliphatic, cyclic or aromatic amines such as me ylamine, dimethylamine, triemylarnine, diethylamine, isopropyldiefhylamine, pyridine and picoline.
  • alkali metal or alkaline-earth metal hydroxides such as sodium, potassium, calcium or magnesium hydroxides
  • ammonia and aliphatic, cyclic or aromatic amines such as me ylamine, dimethylamine, triemylarnine, diethylamine, isopropyldiefhylamine, pyridine and picoline.
  • Illustrative acids which form suitable salts include inorganic acids such as, for example, hydrochloric, hydrobro ic, sulfuric, phosphoric and like acids, and organic carboxylic acids such as, for example, acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic and dihydroxymaleic, benzoic, phenylacetic, 4-aminobenzoic, 4-hydroxybenzoic, anthranilic, cinnamic, salicylic, 4-aminosalicylic, 2- phenoxybenzoic, 2-acetoxybenzoic, mandelic and like acids, and organic sulfonic acids such as methanesulfonic and p-toluenesulfonic acids.
  • inorganic acids such as, for example, hydrochloric, hydrobro ic, sulfuric, phosphoric and like acids
  • organic carboxylic acids such as,
  • stereoisomer is a general term used for all isomers of individual molecules that differ only in the orientation of their atoms in space.
  • stereoisomer includes mirror image isomers (enantiomers), geometric (cis/trans or E/Z) isomers, and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereoisomers).
  • the term "effective inhibitory amount,” is such an amount wherein an enzyme inhibitory effect is achieved to cause a therapeutic effect in a patient.
  • the exact amount of compound to be administered can be readily determined by the attending diagnostician, as one skilled in the art, by the use of conventional techniques and by observing the results obtained under analogous circumstances. Factors significant in determining the dose include: the species of animal, the animal's size, age and general health; the specific disease or disorder involved, the degree of involvement or the severity of the disease; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances. That said, the exact amount employed may vary over a wide range, for example, from about 0.625 to 200 mg/kg of body weight per day, preferably from about 5 to 100 mg/kg of body weight per day.
  • Treat” or “treating” means any treatment, including but not limited to, alleviating symptoms, eliminating the causation of the symptoms either on a temporary or permanent basis, or to preventing or slowing the appearance of symptoms and progression of the named disease, disorder or condition.
  • the term "patient” refers to a warm blooded animal such as a mammal which is afflicted with a particular disease, disorder or condition. It is explicitly understood that guinea pigs, dogs, cats, rats, mice, horses, cattle, sheep, and humans are examples of animals within the scope of the meaning of the term.
  • the active ingredient is preferably incorporated into a composition containing a pharmaceutical carrier, although the compounds are effective and can be administered, in and of themselves.
  • pharmaceutical carrier refers to known pharmaceutical excipients useful in formulating pharmaceutically active compounds for administration, and which are substantially nontoxic and nonsensitizing under conditions of use. The exact proportion of these excipients are determined by the solubility and chemical properties of the active compound, the chosen route of adniinistration as well as standard pharmaceutical practice. That said, the proportion of active ingredient can vary from about 5 to 90% by weight.
  • the pharmaceutical compositions of the invention are prepared in a manner well known in the pharmaceutical arts.
  • the carrier or excipients may be a solid, semisolid or liquid material which can serve as a vehicle or medium for the active ingredient. Suitable carriers or excipients are well known in the art.
  • the pharmaceutical composition may be adapted for oral, inhalation, parenteral or topical use, and may be administered to the patient in the form of tablets, capsules, suspensions, syrups, aerosols, inhalants, suppositories, salves, powders, solutions and the like.
  • the term "pharmaceutical carrier” means one or more excipients.
  • effective routes of administration may include subcutaneously, intravenously, transdermally, intranasally, rectally, vaginally and the like including release from implants as well as direct injection of the active ingredient and/or composition directly into the tissue or tumor sites.
  • suitable pharmaceutical carriers and formulation techniques are found in standard texts, such as Remington: The Science and Practice of Pharmacy, 19 th edition, Volumes 1 and 2, 1995, Mack Publishing Co., Easton, Pennsylvania, U.S.A., which is herein incorporated by reference.
  • the compounds can be formulated into solid or liquid preparations, with or without inert diluents or edible carriers, such as capsules, pills, tablets, troches, powders, solutions, suspensions or emulsions.
  • the capsules, pills, tablets, troches and the like may also contain one or more of the following adjuvants: binders such as microcrystalline cellulose, gum tragacanth; excipients such as starch or lactose, disintegrating agents such as alginic acid, corn starch and the like; lubricants such as stearic acid, magnesium stearate or Sterotex®, (Stokely-Van Camp Inc., Indinapolis, Indiana) glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; and flavoring agents such as peppermint, methyl salicylate or fruit flavoring.
  • a liquid carrier such as polyethylene glycol or a fatty oil. Materials used should
  • the compound may be administered as injectable dosages of a solution or suspension of the compound in a physiologically acceptable diluent with a pharmaceutical carrier which can be a sterile liquid such as water-in-oil or without the addition of a surfactant and other pharmaceutically acceptable excipients.
  • a pharmaceutical carrier which can be a sterile liquid such as water-in-oil or without the addition of a surfactant and other pharmaceutically acceptable excipients.
  • Illustrative oils which can be employed in the preparations are those of petroleum, animal, vegetable or synthetic origin such as, for example, peanut oil, soybean oil and mineral oil.
  • water, saline, aqueous dextrose and related sugar solutions, ethanol and glycols, such as propylene glycol are preferred liquid carriers, particularly for injectable solutions.
  • the parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of inert plastic or glass.
  • solutions or suspensions described above may also include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents, antibacterial agents such as ascorbic acid or sodium bisulfite; chelating agents such as efhylenediaminetetra-acetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • sterile diluents such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents, antibacterial agents such as ascorbic acid or sodium bisulfite
  • chelating agents such as efhylenediaminetetra-acetic acid
  • buffers such as acetates, citrates or phosphates and agents for the
  • the compounds can be administered in the form of a cutaneous patch, a depot injection or implant preparation which can be formulated in such a manner as to permit a sustained release of the active ingredient.
  • the active ingredient can be compressed into pellets or small cylinders and implanted subcutaneously or intramuscularly as depot injections or implants.
  • Implants may employ inert materials such as biodegradable polymers and synthetic silicones. Further information on suitable pharmaceutical carriers and formulation techniques are found in standard texts such as Remington: The Science and Practice of Pharmacy, 19 edition, Volumes 1 and 2, 1995, Mack Publishing Co., Easton, Pennsylvania, U.S.A.
  • DIBALH diisobutylalurninum hydride
  • DMAP 4- dimethylaminopyridine
  • DMF dimethylformamide
  • LAH lithium aluminum hydride
  • LHMDS lithium hexamethyldisilazide
  • NBS N-bromosuccinimide
  • PCC pyidinium chlorochromate
  • PDC pyridinium dichromate
  • Pyr-S0 3 sulfur trioxide pyridine complex
  • TBAF tetrabutylammorrium fluoride
  • TBDMS t-butyldimethyl-silyl
  • TEA triethylamine
  • THF tetrahydrofuran
  • Ac 2 0 acetic anhydride
  • TsOH tosic acid (p-toluenesulphonic acid);
  • the unsubstituted steroid-5-en-3-ols of this invention may be prepared by as depicted in Scheme A.
  • Protecting the hydroxyl group of dehydroepiandrosterone (Al) by reaction with t-butyldimethylsilyl chloride gives silyl ether A2.
  • Wittig reaction on the C ⁇ ketone of A2 with the ylid formed by reaction of triethyl 2- fluoro-2-phosphonoacetate with a suitable base such as lithium hexamethyldisilazide gives vinyl fluoride ester A3 as a mixture of E- and Z-isomers.
  • a suitable base in this instance is any base that will function to form a ylid by reaction with triethyl 2-fluoro-2-phosphonoacetate such as, for example, lithium hexamethyldisilazide, alkyl lithium bases such as t-butyllitbium, potassium t-butoxide and the like. Separation of the isomers is possible, but difficult at this point, so it is usually done after the next step. Reduction of ester A3 is accomplished with a suitable reducing agent such as diisobutylaluminum hydride in dichloromethane to give a mixture of hydroxymethyl vinyl fluorides which are separated into the individual E- and Z-isomers A4 and A5, respectively.
  • a suitable reducing agent such as diisobutylaluminum hydride in dichloromethane
  • the C 2 ⁇ substituted steroid-5-en-3-ols of this invention may be prepared following the methodology depicted in Scheme B.
  • the mixture of vinyl fluoride esters A3 as starting material, the following transformations can be accomplished.
  • the silyl group of A3 is removed using tetrabutylammonium fluoride giving alcohol B12.
  • the latter is oxidized with pyridinium chlorochromate (see Parish, E.J. and Honda, H. Syn. Commun., 1990, 20, 1167-1174) to give conjugated ketone B13.
  • Reduction of the ester group of compound B13 required a two step sequence.
  • Ci substituted steroid-4-en-3-ones of this invention may be prepared as depicted in Scheme C.
  • the starting l ⁇ -alkylandrost-5-ene-3,17-diones (C19) are prepared from androsta-l,4-diene-3,17-dione (C18) according to Westermann and Nickisch (Westermann, J. and Nickisch, K., 1993, Angew. Chem. Int. Ed. Engl, 32, 1389-1370).
  • the enone C19 is then protected as a dienol ether by treating C19 with trimethyl orthoformate in the presence of tosic acid.
  • the resulting dienol ether €20 is reacted with the ylid formed by reaction of triethyl 2-fluoro-2-phosphonoacetate with base to give the vinyl fluoride C21.
  • Diisobutylaluminum hydride reduction of the ester group in C21, followed by acid catalyzed hydrolysis of the dienol ether gives the desired 21-hydroxy-20 ⁇ -fluoro-l ⁇ -methylpregna-4,17(20)-dien-3-one (C23).
  • Similar hydrolysis of the dienol ether €21 gives the corresponding 20 ⁇ -fluoro-l ⁇ -methyl-pregna-4,17(20)-dien-3-on-21-oic acid ethyl ester (C24).
  • Ci substituted steroid-5-en-3-ols of this invention may be prepared as depicted in Scheme D.
  • the starting material, 20 ⁇ -fluoro-l ⁇ -methylpregna-4,17(20)-dien-3-on-21-oic acid ethyl ester (C24a) is first converted to the 3,5-dienol acetate D25a using acetic anhydride in refluxing toluene with a strong acid such as perchloric or tosic acid as a catalyst. Reduction of the 3,5-dienol acetate moiety with sodium borohydride is known to give the corresponding 5-en-3-/3ol, which, in this case, affords compound D26a.
  • the C2 substituted steroid-4-en-3-ones of this invention may be prepared as depicted in Scheme E.
  • Enone E29 is first protected as a dienol ether by treating E29 with trimethyl orthoformate in the presence of tosic acid.
  • the resulting dienol ether E30 is reacted with the ylid formed by reaction of triethyl 2-fluoro-2-phosphonoacetate with base to give the vinyl fluoride ester E31.
  • Diisobutylaluminum hydride reduction of the ester group, followed by acid catalyzed hydrolysis of the dienol ether gives the desired 21-hydroxy-20 ⁇ -fluoro-2 ⁇ -alkylpregna-4,17(20)-dien-3-ones (E33a and E33b).
  • the C 2 substituted steroid-5-en-3-ols of this invention may be prepared as depicted in Scheme F.
  • the starting 20 ⁇ -fluoro-2 ⁇ -alkylpregna-4,17(20)-dien-3-on-21-oic acid ethyl esters (E34a-c) are converted to the 3,5- dienol acetates F35 using acetic anhydride in refluxing toluene with a strong acid such as perchloric or tosic acid as a catalyst. Reduction of F35 with sodium borohydride gives the corresponding steroid-5-en-3-ols F36.
  • the C4 substituted steroid-4-en-3-ones of this invention may be prepared as depicted in Scheme G2.
  • the starting point for the synthesis of each of these compounds is the appropriately substituted 4-alkytestosterone derivatives whose syntheses are detailed in Scheme Gl.
  • Transformation of the various 4-substituted steroid 4-en-3-ones G41a-e to vinyl fluorides G44a-e is shown in Scheme G2 and follows the general strategy previously developed.
  • the steroid 4-en-3-one C41 is first protected as a dienol ether treating G41 with trimethyl orthoformate in the presence of tosic acid.
  • the protected steroid G43 is then reacted with the ylid formed by reaction of triethyl 2-fluoro-2-phosphonoacetate with base to give the vinyl fluoride ester G44.
  • Diisobutylaluminum hydride reduction of the ester group of G44, followed by acid catalyzed hydrolysis of the dienol ether gives the desired 21-hydroxy-20 ⁇ -fluoro-4-substituted-pregna- 4,17(20)-dien-3-ones (G46a-e).
  • Similar acid hydrolysis of the dienol ether moiety of vinyl fluoride esters G44a- e gives the corresponding 20 ⁇ -fluoro-4-substituted-pregna-4,17(20)-dien-3-on-21-oic acid ethyl esters (G47a-e).
  • the C4 substituted steroid-5-en-3-ols described in this invention may be prepared as depicted in Scheme H.
  • Starting materials are the 20 ⁇ -fluoro-4-alkylpregna-4,17(20)-dien-3-on-21-oic acid ethyl esters (G47a-e) described in Scheme G2.
  • the steroid 4-en-3-ones G47 are first converted to the 3,5- dienol acetates H51 using acetic anhydride in refluxing toluene with a strong acid such as perchloric or tosic acid as a catalyst.
  • the C 6 substituted steroid-5-en-3-ols described in this invention may be prepared as depicted in Scheme J.
  • Starting materials are the 20 ⁇ -fluoro-6-alkylpregna-4,17(20)-dien-3-on-21-oic acid ethyl esters (I61a-c) described in Scheme I.
  • the steroid 4-en-3-ones (161 a-c) are first converted to the 3,5-dienol acetates J62a-c using acetic anhydride in refluxing toluene with a strong acid such as perchloric or tosic acid as a catalyst.
  • the starting C 7 ⁇ -alkylandrost-4-ene-3,17-diones (K67a-d) and C ⁇ -alkylandrost-4-ene-3,17-diones (K67e-h) are synthesized starting from the known C substituted steroids K66a-h (Grunwell, J.E., Benson, H.D., Johnston, J.O. and Petrow, V. Steroids, 1976, 27, 760-771) which in turn are prepared from 6- dehydrotestosterone (K65) by the method of Benson and coworkers (loc. cit).
  • the C 3 carbonyls are protected as dienol ethers K68a-h (see Scheme K).
  • Scheme L outlines the syntheses of C 7 substituted steroid-5-en-3-ols.
  • the selectively C 3 protected C - alkylandrost-5-en-3,17-diols (L76a-d) and C7 ⁇ -alkylandrost-5-en-3,17-diols (L76e-h) are synthesized starting from the known C 7 substituted steroids L74a-h (Grunwell, J.E., Benson, H.D., Johnston, J.O. and Petrow, V. Steroids, 1976, 27, 760-771) by borohydride reduction of L74a-h to give L75a-h.
  • 3 ⁇ -Hydroxyandrosta-5,15-dien-17-one (Scheme M, M81) is prepared by the method of Reeder and Joannou (Reeder, A.Y. and Joannou, G.E., Steroids, 1996, 61, 74-81) and used as starting material for the preparation steroids containing an additional double bond at C15 as shown in Scheme M.
  • Alcohol M81 is first silylated by reaction with f-butyldimethylsilyl chloride to give silyl ether M82.
  • Ci5-alkyl-androst-5-en-17-ones which serve as starting materials for the 5 substituted steroids of this invention, are synthesized in two steps from 3 ⁇ -hydroxyandrost-5,15-dien-17-ones M81 as shown in Scheme N..
  • Wittig reaction on C 17 ketones N88a-c with the ylid formed by reaction of triethyl 2-fluoro-2- ⁇ hosphonoacetate with base gives vinyl fluoride esters N89a-c as mixtures of E- and Z-isomers.
  • isolate A5 (1.10 g, 16%) as a white solid: mp 174-176°C.
  • TLC Rf 0.29, ethyl acetate/ hexane
  • EXAMPLE 2a 20 ⁇ -Fluoro-3 ⁇ -hydroxypregna-5,17(20)-dien-21-oic Acid, Ethyl Ester (B12) Add tetrabutylammonium fluoride (45.0 mL of a 1.0M solution in THF, 45.0 mmol) to compound A3 (7.3 g, 14.87 mmol) and stir the resultant solution at room temperature for 30 hours. Slowly add the reaction solution to vigorously stirred cold water (750 mL), filter the resultant suspension and dry to give crude B12. Purify B12 by flash chromatography.
  • EXAMPLE 2b 20 ⁇ -Fluoropregna-4,17(20)-dien-3-on-21-oic Acid, Ethyl Ester (B13) Dissolve alcohol B12 (7.14 g, 18.96 mmol) in benzene (200 mL) and add 3A molecular sieves (1 g). Add pyridinium chlorochromate (81.7 g, 0.379 mol) and reflux the mixture under an argon atmosphere for 5 hours with mechanical stirring. Decant the benzene solution, and wash the residue with ether (4x200 mL). Combine the organic layers, wash with saturated brine, dry, filter, concentrate and purify the residue by flash chromatography to give B13.
  • Dissolve ester A3 (5.0 g, 10.2 mmol) in anhydrous diethyl ether (200mL) and THF (100 mL). Cool the resulting solution in an ice-water bath and treat with methylmagnesium bromide (13.5 mL of a 3.0M solution in ether, 40.5 mmol). Quench the reaction after 4 hours by pouring the reaction mixture into cold water (200 mL) containing acetic acid (10 mL). Separate the aqueous layer and extract with ether (2x200 mL). Wash the combined organic layer and ether extract with water, dry, filter and concentrate to give a solid. Purify the solid by flash chromatography to afford B16 as a mixture of stereoisomers.
  • C23a 20 ⁇ -Fluoro-21-hydroxy-l ⁇ -methylpregna-4,17(20)-dien-3-one
  • C23b 20 ⁇ -Ethyl-20 ⁇ -fluoro-21-hydroxypregna-4,17(20)-dien-3-one
  • C23c 20 ⁇ -Fluoro-21 -hydroxy- 1 ⁇ -propylpregna-4, 17(20)-dien-3-one
  • EXAMPLE 4a 3-Acetoxy-20 ⁇ -fluoro-l ⁇ -methylpregna-3,5,17(20)-triene-21-oic Acid Ethyl Ester (D25a) Stir a solution of ethyl 20 ⁇ -fluoro-l ⁇ -methylpregna-4,17(20)-dien-3-on-21-oic acid ethyl ester (C24a, 2.5 g, 6.43 mmol) in ethyl acetate (250 mL), acetic anhydride (25 mL) and 70% perchloric acid (0.10 mL) at room temperature for 1 hour. Extract the solution with saturated sodium bicarbonate (100 mL) and brine (100 mL).
  • D27a 20 ⁇ -Fluoro-l -methylpregna-5,17(20)-diene-3 ⁇ ,21-diol
  • D27b 20 ⁇ -Fluoro-l ⁇ -propylpregna-5,17(20)-diene-3 ⁇ ,21-diol
  • EXAMPLE 5b The experimental procedure for the synthesis of E30a-b from steroid-4-en-3-ones E29a-b can be found in General Procedures 1.
  • EXAMPLE 6a 3-Acetoxy-20 ⁇ -fluoro-2 ⁇ -methylpregna-3,5,17(20)-triene-21-oic acid ethyl ester (F35a) Stir a solution of 20 ⁇ -fluoro-2 ⁇ -methylpregna-4,17(20)-dien-3-on-21-oic acid ethyl ester (E34a, 2.5 g, 6.43 mmol) in ethyl acetate (250 mL), acetic anhydride (25 mL) and 70% perchloric acid (0.10 mL) at room temperature for 1 hour. Extract the solution with saturated sodium bicarbonate (100 mL) and brine (100 mL).
  • F35a which one can purify by crystallization or use directly in the next step.
  • the following compounds may be prepared: 3-acetoxy-2 ⁇ -ethyl-20 ⁇ -fluoropregna-3,5,17(20)-triene-21-oic acid ethyl ester (F35b) 3-acetoxy-20 ⁇ -fluoro-2 ⁇ -pro ⁇ ylpregna-3,5,17(20)-triene-21-oic acid ethyl ester (F35c)
  • EXAMPLE 6b 20 ⁇ -Fluoro-3 ⁇ -hydroxy-2 ⁇ -methylpregna-5,17(20)-dien-21-oic acid ethyl ester (F36a) Add sodium borohydride (0.40 g, 10.6 mmol) to a solution of 3-acetoxy-20 ⁇ -fluoro-l ⁇ -methylpregna- 3,5,17(20)-triene-21-oic acid ethyl ester (F35a, 2.23 g, 5.18 mmol) in ethanol (400 mL) and tetrahydrofuran (just enough to effect solution). Stir overnight and add formic acid dropwise until gas evolution ceases.
  • EXAMPLE 7a 17 ⁇ -Hydroxy-4-(2-propyl)androst-4-en-3-one (G38c) Stir and treat a cooled (0°C in a salt-ice bath) solution of 4-nor-4-oxasteroid G40 (7g, 21.1 mmol) in ether (100 mL) and tetrahydrofuran (30 mL) with 2N isopropyl-magnesium bromide in ether (15 mL, 30 mmol). Stir the reaction for 18 hours and pour into cold water (500 mL): Acidify the mixture by addition of 10% hydrochloric acid. Remove the aqueous layer and extract with ether (3x150 mL).
  • EXAMPLE 7b 4-(2-propyl)androst-4-ene-3, 17-dione (G41c) Cool a solution of alcohol G38c (2.20 g, 6.70 mmol) in acetone (200 mL) to 3 °C in an ice-water bath. Add Jones reagent (ca 3 mL, Djerassi, C, Engle, R.R. and Bowers, A., J. Org. Chem., 1956, 21, 1547) until the greenish color persists. Decompose excess reagent by addition of isopropanol. Remove the solids by filtration and wash with acetone. Combine the filtrate, wash and concentrate to a greenish gum. Purify the gum by flash chromatography to give 4-(2-propyl)androst-4-ene-3, 17-dione (G41c).
  • G50Ba-c Utilizing the procedures described in examples 7g and 7h, one may prepare G50Ba-c from G48Ba-c. 4-Amino-20 ⁇ -fluoro-l ⁇ -methylpregna-4,17(20)-diene-3-one (G50Ba) 4-Amino-20 ⁇ -fluoro-7 ⁇ -methylpregna-4,17(20)-diene-3-one (G50Bb)
  • EXAMPLE 8a 3-Acetoxy-20 ⁇ -fluoro-4-methylpregna-3,5,17(20)-triene-21-oic Acid Ethyl Ester (H51a) Stir a solution of 20 ⁇ -fluoro-4-methylpregna-4,17(20)-dien-3-on-21-oic acid ethyl ester (G47a, 2.5 g, 6.43 mmol) in ethyl acetate (250 mL), acetic anhydride (25 mL) and 70% perchloric acid (0.10 mL) at room temperature for 1 hour. Extract the solution with saturated sodium bicarbonate (100 mL) and brine (100 mL).
  • Example 10a 3-Acetoxy-20 ⁇ -fluoro-6-methyl ⁇ regna-3,5,17(20)-triene-21-oic Acid Ethyl Ester (J62a) Stir a solution of 20 ⁇ -fluoro-6 -methylpregna-4,17(20)-dien-3-on-21-oic acid ethyl ester (I61a, 2.5 g, 6.43 mmol) in ethyl acetate (250 mL), acetic anhydride (25 mL) and 70% perchloric acid (0.10 mL) at room temperature for 1 hour. Extract the solution with saturated sodium bicarbonate (100 mL) and brine (100 mL).
  • J64a 6-Ethyl-20 ⁇ -fluoropregna-5,17(20)-diene-3 ⁇ ,21-diol
  • J64b 6-Butyl-20 ⁇ -fluoropregna-5, 17(20)-diene-3 ⁇ ,21-diol
  • J64c 6-Butyl-20 ⁇ -fluoropregna-5, 17(20)-diene-3 ⁇ ,21-diol
  • EXAMPLE 12a 7 ⁇ -Methylandrost-5-ene-3 ⁇ ,17 ⁇ -diol 17 Acetate (L75a) Add slowly a solution of 7 ⁇ -methylandrost-5-en-3-on-17j3-ol 17 acetate (L74a, 6.3 g, 18.9 mmol) in tetrahydrofuran (50 mL) to a solution of sodium borohydride (0.72 g, 18.9 mmol) in 95% ethanol (200 mL) cooled to -3°C in a salt/ice bath with stirring. Stir at this temperature for 3 hours and decompose the excess reagent by cautious addition of acetic acid (10 mL). Remove the solvents and purify the resulting crude product by flash chromatography to give 7 ⁇ -methylandrost-5-ene-3 ⁇ ,17 ⁇ -diol 17 acetate (L75a) as a white solid. Similarly prepare the following analogs:
  • EXAMPLE 12e 3-[[(l,l-Dimethyletl ⁇ yl)dimethylsilyl]oxy]-20 ⁇ -fluoro-7 ⁇ -methylpregna-5,17(20)-dien-21-ol (L79a) Slowly add diisobutylaluminum hydride (6.75 mL of a 1.OM solution in dichloromethane, 67.5 mmol) to a stirred solution of ester L78a (7.57 g, 15 mmol) in dichloromethane (135 mL) under nitrogen and cooled to - 78°C.
  • EXAMPLE 13a 3 ⁇ -[[(l,l-Dimethylethyl)dimethylsilyl]oxy]androst-5,15-dien-17-one (M82)
  • t-butyldimethylsilyl chloride 5.49 g, 36.4 mmol
  • 4-dimethylaminopyridine 0.21 g, 1.74 mmol
  • triethylamine 5.32 mL, 38.14 mmol
  • EXAMPLE 13c (17Z)-3 ⁇ -[[(l,l-D ⁇ rmemylethyl)dimethylsilyl]oxy]-20-fluoropregna-5,15,17(20)-trien-21-ol (M84) an ⁇ [[(l,l-Dimetl ⁇ yle1 ⁇ yl)d]rmethylsilyl]oxy]-20-fluoropregna-5,15,17(20)-trien-21-ol (M85)
  • EXAMPLE 14c 3 ⁇ -[[(l,l-Dime le l)dimethylsilyl]oxy]-20 ⁇ -fluoro-15 ⁇ -methylpregna-5,17(20)-dien-21-ol (N90a) Slowly add diisobutylaluminum hydride (9.34 mL of a 1.0M solution in dichloromethane, 9.34 mmol) to a stirred, cooled (-78°C) solution of N89a (1.07 g, 2.12 mmol) in dichloromethane (25 mL) under nitrogen.
  • EXAMPLE 14d 20 ⁇ -fluoro-15 -methyl ⁇ regna-5,17(20)-dien-3 ⁇ ,21-ol (N91a)
  • tetrabutylammonium fluoride (0.85 mL of a 1.0M solution in THF, 0.85 mmol)
  • compound N90a (lOOmg, 0.192 mmol)
  • Add the reaction solution dropwise to vigorously stirred water (20 mL) and filter the resultant suspension. Dry the filter cake to give 20 ⁇ -fluoro-15 -methyl ⁇ regna-5,17(20)-dien-3 ⁇ ,21-ol (N91a) a white solid.
  • EXAMPLE 15b 3 ⁇ -[[(l,l-Dime ylethyl)dimethylsilyl]oxy]-20 ⁇ -fluoro-19-norpregna-5,17(20)-dien-21-ol (O99) Slowly add diisobutylaluminum hydride (2.18 mL of a 1.0M solution in dichloromethane, 2.18 mmol) to a stirred, cooled (-78°C) solution of 098 (2.36 g, 4.95 mmol) in dichloromethane (50 mL) under nitrogen.
  • EXAMPLE 15c 20 ⁇ -Fluoro-l 9-norpregna-5, 17(20)-diene-3 ⁇ ,21 -diol (O100)
  • tetrabutylammonium fluoride (14.0 mL of a 1.0M solution in THF, 14.0 mmol)
  • compound 099 0.52 g, 1.50 mmol
  • Add the reaction solution slowly to vigorously stirred cold water (250 mL), filter the resultant suspension and dry the filter cake. Purify the crude material by flash chromatography to give 20 ⁇ -fluoro-19-norpregna-5,17(20)-diene-3 ⁇ ,21-diol (O100).
  • Assays contained 0.05M potassium phosphate, pH 7.4, an NADPH regenerating system (1 mM NADPH, 5 mM glucose-6-phosphate, 1 IU/mL glucose-6-phosphate dehydrogenase), test compound, substrate and microsomal protein in a total volume of 0.2 mL. Control assays contained all components, including DMSO, but no test compound. All assays were performed in duplicate.
  • the reaction was initiated by the addition of substrate, 7- 3 H-17 ⁇ -hydroxypregnenolone (11.2 mCi/mmole; 0.20 mCi per assay) plus unlabeled 17 ⁇ -hydroxypregnenolone dissolved in DMSO, contributing 2.5% v/v to the final assay mix, and phosphate buffer, yielding a final concentration of 0.05 mM 17 ⁇ -hydroxypregnenolone (ca. equal to the K m value) to the other assay components.
  • the complete assay was incubated at 34°C for 6 minutes. Each assay was terminated by addition of 5 mL of chloroform:methanol (2:1) and 0.9 mL water.
  • Carrier steroids representing substrates and products (2.5 ⁇ g each of 17c-hydroxypregnenolone, dehydroepiandrosterone, and androst-5-ene-3
  • the organic phase containing the steroids was evaporated using nitrogen gas, the residues were dissolved in 18% tetrahydrofuran (v/v) in hexane, and the steroids were separated by HPLC on a Si60 (5 mm) column (4x250 mm) using a gradient of 18-22% tetrahydrofuran (v/v) in hexane. Radioactivity in the steroid peaks was measured using a Radiometric Model HS or Model A515 Flo-One detector. The enzyme activity for each assay was calculated from the percent conversion of substrate to products, and the results expressed as percent inhibition of control.
  • the homogenate was sonified in three pulses of 5 seconds each at 50% of maximum power.
  • the homogenate was subjected to differential centrifugation with each supernatant successively centrifuged at 600xG and 9000xG in a Beckman J21 centrifuge followed by 120,000xG in a Beckman Model L5-75 ultracentrifuge.
  • the final pellet, containing the microsomal fraction was reserved and resuspended in 0.05M potassium phosphate buffer, pH 7.0, containing 25% (w/v) glycerol equal to 1 mL per 3 g wet tissue.
  • the suspension was divided into aliquots, flash frozen using dry ice in methanol, and stored at -80°C.
  • Rat prostate tissue was treated in a similar manner as described above except that fresh prostate tissue was removed from male Sprague-Dawley rats (Charles Rivers), 0.05M potassium phosphate buffer, pH 6.6, was used for homogenization and 0.05M potassium phosphate buffer, pH 6.6, containing 25% (w/v) glycerol was used for storage. Protein concentration was determined by the BioRad dye binding method (BioRad, Richmond, California, USA).
  • Assays of human, cynomologus monkey and rat prostatic 5oj-reductase contained 100 mM potassium phosphate-sodium citrate buffer (pH 5.6), 0.1% bovine serum albumin (w/v, Sigma Chemicals), 1.0 mM sodium EDTA, 7-96 ⁇ g of microsomal protein, 1.0 mM NADPH; 5.0 mM glucose-6-phosphate, 1 IU/mL glucose-6- phosphate dehydrogenase, [l,2- 3 H]-testosterone (0.15 ⁇ Ci, DuPont-New England Nuclear,), unlabeled testosterone to yield the desired concentration of substrate, and test compound which was dissolved in DMSO and then diluted in 100 mM potassium phosphate-sodium citrate buffer (pH 6.5) to yield a final assay concentration of 0.1% (v/v) DMSO.
  • the K m values of testosterone ranged from 0.125-0.273 ⁇ M for human 5 ⁇ -reductase, 0.025-0.091 ⁇ M for cynomolgus monkey 5 ⁇ -reductase, and 0.74-0.90 ⁇ M for rat 5 ⁇ -reductase.
  • Each assay was terminated by addition of 5 mL of chloroform:methanol (2:1) and 0.9 mL of water.
  • Carrier steroids representing substrates and products (2.5 ⁇ g each of testosterone, 5 ⁇ -dihydrotestosterone, and 3,17-androstenediol) were added.
  • the steroids were extracted by the method of Moore and Wilson (Methods in Enzymol., eds, O. Malley, B.W. and Hardman, J.G. 36, 466-474 (1975).
  • the organic phase containing the steroids was evaporated using nitrogen gas, the residues were dissolved in 3% isopropanol (v/v) in hexane, and the steroids were separated by normal phase HPLC (LiCrosorb® DIOL derivatized silica gel column (lO ⁇ M; 4x250 mm; EM Sciences, Gibbstown, New Jersey). After injection of sample, the steroids were separated with a 3% to 7.5% isopropanol in hexane gradient over 24 minutes, and then under isocratic conditions for 2 minutes at 75% (v/v) isopropanol in hexane using a flow rate of 1 mL per minute.
  • HPLC LiCrosorb® DIOL derivatized silica gel column
  • the column was re-equilibrated with 3% (v/v) isopropanol in hexane prior to the next injection.
  • the retention times were: 5 ⁇ -dihydrotestosterone, 10.1-11.2 minutes; testosterone, 14.2-16.1 minutes; and 3/3,17/3- androstanediol, 17.1-20.2 minutes.
  • the HPLC system used to separate the steroid components of the human and rat 5 ⁇ -reductase assays consisted of Beckman 114M pumps and a 421A controller, a Waters WISP 710B autosampler, a Kratos Spectraflow 783 UV detector (wavelength set at 238 nm) and a Radiomatic model HS radioactivity analyzer.
  • the HPLC system used for analysis of the cynomolgus monkey 5 ⁇ -reductase assay was composed of a Waters 600E controller and dual pump unit, a Waters WiSP model 715 autosampler, a Waters 486 UV detector (wavelength, 238 nm), and a Radiomatic A515 radioactivity analyzer.
  • FloScint II was used at a ratio of 1.6:1 (scrntillant to column effluent) for detection of [ 3 H]-dihydrotestosterone.
  • FloOne HS radioactivity data from the human and rat 5 ⁇ -reductase assays were analyzed using the Beckman Data Transporter (Beckman Instruments, Fullerton, CA), which transferred integrated data collected from the FloOne HS to a mainframe computer and data were analyzed using RSI (BBN Software Products Corp., Cambridge, MA).
  • Radioactivity data from the FloOne arising from the cynomolgus monkey 5 ⁇ -reductase assays were analyzed using Waters Millenium software. Reaction rates were determined by multiplying the initial testosterone concentration by the percent of dihydrotestosterone and 3 , 17-androstenediol formed.

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Abstract

La présente invention concerne l'ester éthylique de 20κ-fluoroprégna-4,17(20)-dièn-3-on-21-oïque, l'ester éthylique de 20κ-fluoro-3β-hydroxyprégna-4,17(20)-dièn-21-oïque, le 20κ-fluoro-21-hydroxyprégna-4,17(20)-dièn-3-one, le 20κ-fluoroprégna-4,17(20)-dièn-3β,21-diol et les composés s'y rattachant, ainsi que des compositions incorporant ces composés. L'invention concerne également l'inhibition de la C17,20 lyase, de la 5α-réductase et de la C17-hydroxylase, ainsi que l'utilisation de ces composés pour le traitement de troubles dépendant ou à médiation des androgènes et des oestrogènes, et notamment l'hyperplasie bénigne de la prostate, le cancer de la prostate, le cancer du sein et des troubles à médiation du dihydrotestostérone (DHT) tels que l'acné et l'hirsutisme. L'invention concerne en outre le traitement des troubles liés à la synthèse excessive du cortisol, notamment le syndrome de Cushing. Le traitement des troubles dépendants des androgènes inclut également une thérapie associant des antagonistes connus des récepteurs des androgènes, et notament le flutamide. Les composés de l'invention sont représentés par la formule générale (I).
PCT/US2001/019889 2000-06-27 2001-06-21 Steroïdes 20-fluoro-17(20)-vinyliques convenant comme inhibiteurs ce la c17-20-lyase et de la 5-alpha reductase Ceased WO2002000681A1 (fr)

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AU2001268661A AU2001268661A1 (en) 2000-06-27 2001-06-21 20-fluoro-17(20)-vinyl steroids as inhibitors of c17-20-lyase and 5-alpha reductase

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Cited By (5)

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Publication number Priority date Publication date Assignee Title
WO2003020744A1 (fr) * 2001-08-28 2003-03-13 Schering Ag Methylene-4-azasteroides
EP1423407B1 (fr) * 2000-09-04 2006-03-08 Schering AG 4-halogenes steroides de 17-methylene, procede permettant de les produire et compositions pharmaceutiques contenant ces composes
DE102006008074A1 (de) * 2006-02-22 2007-08-23 RUHR-UNIVERSITäT BOCHUM Behandlung von Krebs mit Geruchsrezeptor-Liganden
WO2012110768A1 (fr) 2011-02-18 2012-08-23 The University Of Birmingham Utilisations thérapeutiques des diarylalcanes tels que le mitotane
US9198906B2 (en) 2006-10-02 2015-12-01 Cortendo Ab (Publ) Ketoconazole enantiomer in humans

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WO1998033506A1 (fr) * 1997-02-05 1998-08-06 University Of Maryland At Baltimore Inhibiteurs de synthese d'androgenes

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US3361743A (en) * 1966-04-04 1968-01-02 Searle & Co Optionally substituted hydrazones of 3-oxygenated pregna-5, 17(20)-dien-21-als
WO1998033506A1 (fr) * 1997-02-05 1998-08-06 University Of Maryland At Baltimore Inhibiteurs de synthese d'androgenes

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DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; KANEKO, HIDEHIKO ET AL: "Carbalkoxymethylene steroids", XP002178583, retrieved from STN Database accession no. 70:88104 *
DATABASE WPI Section Ch Derwent World Patents Index; Class B00, AN 1966-33967F, XP002178584 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1423407B1 (fr) * 2000-09-04 2006-03-08 Schering AG 4-halogenes steroides de 17-methylene, procede permettant de les produire et compositions pharmaceutiques contenant ces composes
AU2002210470B2 (en) * 2000-09-04 2006-07-20 Schering Ag 4-halogenated 17-methylene steroids, method for the production thereof and pharmaceutical compositions containing these compounds
WO2003020744A1 (fr) * 2001-08-28 2003-03-13 Schering Ag Methylene-4-azasteroides
US7186728B2 (en) 2001-08-28 2007-03-06 Schering Ag Methylene-4-azasteroids
DE102006008074A1 (de) * 2006-02-22 2007-08-23 RUHR-UNIVERSITäT BOCHUM Behandlung von Krebs mit Geruchsrezeptor-Liganden
DE102006008074B4 (de) * 2006-02-22 2013-08-14 RUHR-UNIVERSITäT BOCHUM Behandlung von Krebs mit Geruchsrezeptor-Liganden
US9198906B2 (en) 2006-10-02 2015-12-01 Cortendo Ab (Publ) Ketoconazole enantiomer in humans
WO2012110768A1 (fr) 2011-02-18 2012-08-23 The University Of Birmingham Utilisations thérapeutiques des diarylalcanes tels que le mitotane

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